Science
A novel perspective on how HLA genes influence immune responses to cancer
Despite advances in active cancer immunotherapy, predicting the immune system's response to cancer remains challenging, leading to uncertainty in selecting new immunotherapeutic targets.
To explore this further, TREOS scientists studied the relationship between the immune responses of clinical trial participants and their complete HLA genotype (meta-analysis of 94 cancer vaccine clinical trials). Their findings revealed that a person's complete HLA genotype, rather than individual HLA alleles, is a key factor in determining immune responses (Lorincz et al., Cells, 2021).
Specifically, we identified "promiscuous epitopes" (PEPIs), that bind to multiple MHC molecules of a person. These PEPIs serve as genetic biomarkers, for the first time accurately predicting individual’s T cell responses (Hubbard et al., CCR, 2022).
TREOS proposes that PEPIs could serve as key targets for the design of effective immunotherapies, as they help the immune system to efficiently recognize cancer cells (abundantly presented targets) and elicit strong and broad immune responses (polyclonal T cell responses), potentially breaking the tolerance. The PEPIs may also be useful in predicting which patients will respond to our peptide-based cancer vaccines, enabling more personalized treatments using PEPI as biomarker.
Why is PEPI Technology Unique?
Optimized Immune Targets
PEPIs bind multiple MHC molecules of a person, therefore trigger exceptionally strong immune responses against tumor antigens — far surpassing the effectiveness of “common” epitopes.
Clinical Outcome Correlation
Strong correlation observed between PolyPEPI induced immune responses and clinical outcomes in each of Treos’ clinical trials.
Novel Biomarker
PEPIs serve as genetic biomarkers using a simple saliva or blood sample, enabling rapid identification of likely responders.
Broad Patient Accessibility
PEPIs enable the development of off-the-shelf cancer vaccines that are effective across a genetically diverse patient population. The low cost and strong safety record makes PolyPEPI treatments accessible to patients worldwide.
Synergistic with Other Therapies
PEPIs enhance the efficacy of other anti-cancer treatments, such as chemotherapies, checkpoint inhibitors and others, without compromising their safety or toxicity profiles.
Biomarker-Driven Immunotherapy Development
PEPIs drive the unprecedented immune reactions and clinical outcomes seen in our studies (Hubbard et al., ESMO2024). As a result, PEPIs are a central focus of our vaccine design platform and are incorporated into our product pipeline.
Our Personal Antigen Selection Calculator (PASCal) tool enables the creation of effective peptide-based cancer immunotherapies for various solid tumors. PASCal connects HLA genetics to the expression of shared tumor antigens in thousands of real-world patients, allowing us to account for the diversity in tumors and patient genetics (Lorincz et al., SITC 2021).
PASCal helps us develop off-the-shelf immunotherapies incorporating multiple PEPIs, that are effective for a wide range of people, regardless of their genetic background. This technology enables us to create cancer immunotherapies that do not exclude patients lacking prevalent HLA alleles (eg. HLA-A2), making them accessible to a broader patient population.
In addition, our proprietary PEPI biomarker uniquely allows TREOS to apply these off-the-shelf products to personalized cancer treatments. With just a simple saliva or blood sample—no tumor biopsy needed—we can select likely responders to our products or tailor treatments to individual patients.